{"doi":"10.1172/jci193354","title":"PPP2R2A insufficiency enhances PD-L1 immune checkpoint blockade efficacy in lung cancer through cGAS-STING activation","abstract":"PP2A B55α, a regulatory subunit of protein phosphatase 2 (PP2A), is underexpressed in greater than 40% of non-small cell lung cancer (NSCLC) cases due to loss of heterozygosity of PPP2R2A, the gene encoding this protein. Given that low PPP2R2A expression correlates with poor prognosis, treating PPP2R2A-deficient NSCLC represents an unmet medical need. Here, we show that PPP2R2A knockdown or its heterozygosity (PPP2R2A+/-) increases cytosolic DNA, leading to cGAS-STING-type I IFN pathway activation. PPP2R2A deficiency results in elevated expression of immune checkpoint protein PD-L1 via GSK-3β- and STING-dependent mechanisms. PPP2R2A+/- cancer cells have enhanced sensitivity to PD-L1 blockade in a mouse model of lung cancer due to modulation of the tumor immune microenvironment, resulting in increased NK cells and reduced infiltration and function of Tregs. Consequently, PD-L1 antibody treatment increases CD8+ T infiltration and activity, especially in tumors with PPP2R2A heterozygosity. Furthermore, systemic or Treg-specific IFNAR1 blockade reduces the efficacy of PD-L1 blockade in PPP2R2A+/- tumors. Patients with NSCLC with a low PPP2R2A/PD-L1 ratio respond better to immune checkpoint blockade (ICB). These findings underscore the therapeutic potential of ICB in treating PPP2R2A-deficient NSCLC and suggest that PPP2R2A deficiency could serve as a biomarker for guiding ICB-based therapies.","journal":"Journal of Clinical Investigation","year":2025,"id":522454,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":809698,"name":"No Joon Song","orcid":null,"position":1,"is_corresponding":false},{"id":1393988,"name":"Anqi Li","orcid":"0000-0003-3182-1971","position":2,"is_corresponding":false},{"id":1223653,"name":"Deepika Singh","orcid":"0000-0001-5347-6713","position":3,"is_corresponding":false},{"id":857693,"name":"Chandra Bhushan Prasad","orcid":"0000-0001-9995-2666","position":4,"is_corresponding":false},{"id":277604,"name":"Chunhong Yan","orcid":"0000-0002-3974-7991","position":5,"is_corresponding":false},{"id":251305,"name":"David P. Carbone","orcid":"0000-0003-3002-1921","position":6,"is_corresponding":false},{"id":889173,"name":"Qi-En Wang","orcid":"0000-0001-6220-1404","position":7,"is_corresponding":false},{"id":1393989,"name":"Xiaoli Zhang","orcid":"0000-0001-7977-7565","position":8,"is_corresponding":false},{"id":270306,"name":"Zihai Li","orcid":"0000-0003-4603-927X","position":9,"is_corresponding":false},{"id":356390,"name":"Junran Zhang","orcid":"0000-0001-5413-3675","position":10,"is_corresponding":false},{"id":1223652,"name":"Zhaojun Qiu","orcid":"0000-0001-8582-5068","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:49:54.058858Z","pmid":"41411055","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}